Design, synthesis and biological evaluation of novel tetrahydroisoquinoline quaternary derivatives as peripheral κ-opioid receptor agonists

Ting Guo; Zongjie Gan; Jie Chen; Dechuan Wang; Ling He; Qiao Song; Yungen Xu

doi:10.1016/j.bmc.2016.05.002

Design, synthesis and biological evaluation of novel tetrahydroisoquinoline quaternary derivatives as peripheral κ-opioid receptor agonists

Bioorg Med Chem. 2016 Jul 1;24(13):2964-2970. doi: 10.1016/j.bmc.2016.05.002. Epub 2016 May 3.

Authors

Ting Guo¹, Zongjie Gan², Jie Chen³, Dechuan Wang¹, Ling He⁴, Qiao Song², Yungen Xu⁵

Affiliations

¹ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
² Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
³ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
⁵ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].

PMID: 27185012
DOI: 10.1016/j.bmc.2016.05.002

Abstract

A novel series of tetrahydroisoquinoline quaternary derivatives 4 were synthesized as peripheral κ-opioid receptor agonists. All the target compounds were evaluated in κ-opioid receptor binding assays, and compounds 4l, 4m, and 4n exhibited high affinity for κ-opioid receptor. Furthermore, compound 4l (κKi=0.94nM) produced potent antinociceptive activity in the mouse acetic acid-induced writhing assay, with lower sedative side effects than the parent compound MB-1c.

Keywords: Peripheral; Tetrahydroisoquinoline quaternary derivatives; κ-Opioid receptor agonists.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetic Acid
Analgesics / chemical synthesis
Analgesics / chemistry
Analgesics / pharmacology
Animals
Drug Design*
Hypnotics and Sedatives / chemical synthesis
Hypnotics and Sedatives / chemistry
Hypnotics and Sedatives / pharmacology
Mice
Molecular Structure
Pain / chemically induced
Pain / drug therapy*
Protein Binding / drug effects
Receptors, Opioid, kappa / agonists*
Tetrahydroisoquinolines / chemical synthesis*
Tetrahydroisoquinolines / chemistry
Tetrahydroisoquinolines / pharmacology
Tetrahydroisoquinolines / therapeutic use*

Substances

Analgesics
Hypnotics and Sedatives
Receptors, Opioid, kappa
Tetrahydroisoquinolines
Acetic Acid